The long term objectives of this project are to contribute to the understanding of the molecular mechanisms of chemical carcinogenesis induced by polycyclic aromatic hydrocarbons (PAHs) through the synthesis of biologically significant metabolites of these PAHs, and the study of their chemical and biological properties and reactions with various nucleophiles including DNAs. During the last grant award period, we have firmly established a totally novel, efficient, generally applicable synthetic method towards the diol epoxide and trans-dihydrodiol metabolites of PAHs. With these successful results in hand, we now wish to turn our focus to even more challenging synthetic and bioorganic and biomechanistic aspects of PAH chemical carcinogenesis. The specific aims for the next grant award period will be: 1) extension of the aryne-3,4-dibenzyloxyfuran cycloaddition method we have developed to the synthesis of optically active bay region syn- and anti- diol epoxides and other metabolites of highly potent carcinogenic PHAs. These PAHs include: benzo[a]pyrene, 7-methyl, and 7,12-dimethylbenz[a]- anthracene, and 3-methylcholanthrene, 2) synthesis of the optically active bay-region diol epoxide and other metabolites of the potent carcinogen 15,16-dihydro-11- methylcyclopenta[a]phenanthren-17-one and its desmethyl analog, 3) synthesis of [3-13C]-cyclopenta[cd]pyrene 3,4-oxide and the use of this epoxide and [2-13C]-naphthalene 1,2-oxide in the study of molecular mechanisms in epoxide hydrolase and glutathione transferase (the former only) reactions, 4) reactions of these metabolites with various nucleophiles in order to obtain pertinent information on their chemical reactivity. These include solvolytic reactions in aqueous solutions and in vitro covalent interactions with DNAs, 5) synthesis of DNA oligomers modified by BP bay region diol epoxides at the specific base sites and elucidation of their molecular conformations. All of the synthetic metabolites will be submitted for extensive biological testings to our collaborators.